The neurotransmitter histamine (HA) causes analgesia when administered directly into the various brain areas, including the periaqueductal grey (PAG), an important site of action of morphine (MOR). Recent studies from this lab show that: 1) HA H2 receptor antagonists attenuate MOR analgesia, and 2) MOR enhances brain HA turnover, consistent with the hypothesis that activation of brain H2 receptors is important in the expression of MOR analgesia. The present proposal will clarify the role of histaminergic neurons in analgesic responses, and will identify the sites and mechanisms of action of HA-related drugs on these responses. To test directly the hypothesis that activation of brain H2 receptors is important for the expression of MOR analgesia, intraventricular (ivt) does-response curves will be determined for 11 H2 antagonists (of varying chemical structure and H2 potency) as inhibitors of MOR analgesia. The H2 antagonist cimetidine potentiates, rather than inhibits Mor analgesia; it will also be determined if this effect is a result of this drug's documented ability to inhibit MOR metabolism. To identify the CNS site (s) where H2 antagonists act to inhibit MOR analgesia, the effects of combinations of intracerebral, intrathecal and systemic administration of H2 antagonists and MOR will be studied. To pharmacologically classify the analgesia elicited by ivt and intracerebral HA, the effects of HA agonists (alone) and antagonists (in the presence of HA) will be assessed on antinociceptive responses. To determine the anatomical and pharmacological relationship(s) between histaminergic and opiate analgesia, the effects of acute and chronic combinations of HA and MOR will be determined. To characterize the neurochemical effects of MOR on brain HA dynamics, the actions of systemic MOR will be assessed on the levels and turnover of HA and its metabolites in brain regions and spinal cord. To learn the relationship between MOR analgesia and MOR's actions on HA turnover, pharmacological and microinjection experiments with MOR and HA turnover will be performed. To test the hypothesis that agents capable of altering histaminergic activity should modify analgesic responses, the effects of drugs that modify HA synthesis, HA metabolism, and neuronal HA release will be determined on antinociceptive tests in the presence and absence of MOR. These studies will enhance our knowledge of antinociceptive mechanisms, and may lead to the development of novel, clinically useful agents for the relief of pain.